Mammalian ovary provides not only eggs for reproduction, but also female hormones to maintain normal physiology. However, many pathological conditions in the ovary result in female infertility and diseases such as ovarian cancer. My long-term goal is to identify molecules that contribute to the physiological and pathological changes in the ovary so that novel diagnostic or therapeutic methods can be developed for improving women's health. Estrogen (E2) plays an important role in ovarian physiology and pathology, but the mechanisms are still unclear. GPR30 has been implied as a membrane estrogen receptor (mER) in many cells and tissues. We have shown that GPR30 is expressed in the hamster ovary and functions as a membrane estrogen receptor (mER) to regulate ovarian follicle formation and development. However, the mechanism underlying GPR30-mediated estrogen regulation of follicle development is still unknown. Similarly, whether GPR30 plays a role in ovarian carcinogenesis is equally unclear. I hypothesize that estrogen, acting via GPR30, regulates ovarian cell proliferation, differentiation and survival under both physiological (regulation of follicle formation and development) and pathological (ovarian carcinogenesis) conditions. This proposal will focus on the mechanisms of GPR30-mediated estrogen action on the regulation of primordial follicle formation (K99 phase), and on the function of GPR30 in ovarian cancer progression (R00 phase). The specific aims are: 1) to examine the GPR30-mediated E2 action on the proliferation, differentiation, communication and survival of ovarian cells during primordial follicle formation, 2) to examine the signaling mechanisms whereby GPR30 mediates E2 action in ovarian somatic cells, and 3) to determine the expression of GPR30 in ovarian cancer tissues and the function of GPR30 in the proliferation, invasion and metastasis of ovarian cancer cells. Achievement of this K99/R00 program will shed light on the mechanism of physiological and pathological regulation of ovarian cell functions by GPR30, provide valuable information for drug discovery and the development of improved therapy for estrogen-related reproductive diseases such as premature ovarian failure (POF) and ovarian cancer, and facilitate transition of my career from a postdoctoral trainee to independent investigator. PUBLIC HEALTH RELEVANCE: Accomplishment of this project will uncover the mechanisms of GPR30-mediated estrogen action on the regulation of ovarian cell activities under both the physiological and pathological conditions, enrich our knowledge on the membrane estrogen receptor biology and provide new targets for drug discovery, development of new diagnostic tools and advanced management of ovarian cancer.